Protein Disulfide Isomerases

Abstract

Abstract Protein disulfide isomerase (PDI) is a multifunctional protein that facilitates the formation of correct disulfide crosslinks between cysteine residues during the early stages of protein folding and secretion in the endoplasmic reticulum. It is a member of a large family of oxidoreductases that catalyse exchange reactions between thiols and disulfides. PDI is a multidomain protein, consisting of four tandem thioredoxin domains. The N ‐ and C ‐terminal thioredoxin domains have catalytic disulfide/dithiol centers while the two internal domains are structural and provide additional interactions with the protein substrates. The catalysis of disulfide formation relies almost entirely on the high reactivity of PDI's active site disulfides. However, the ability to catalyse disulfide isomerisation requires multiple domains. In the cell, PDI's essential activity is the formation of disulfide bonds, but it does catalyse isomerisation. Key Concepts: PDI structure consists of four tandem thiredoxin domains. The ability to form disulfides between cysteines in substrate proteins results from highly reactive active site disulfides. PDI can correct (isomerise) misformed disulfides by reducing incorrect disulfides and reoxidising in a different configuration. The multidomain structure is needed for catalysis of isomerisation but a single catalytic domain is sufficient to catalyse substrate oxidation. In the cell, the essential activity of PDI is its ability to form substrate disulfides.